basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) and similar proteins; ARNTL, also termed Basic-helix-loop-helix-PAS protein MOP3, or brain and muscle ARNT-like 1 (BMAL1), or Class E basic helix-loop-helix protein 5 (bHLHe5), or member of PAS protein 3, or PAS domain-containing protein 3 (PASD3), or bHLH-PAS protein JAP3, is a member of the bHLH-PAS transcription factor family that forms heterodimers with another bHLH-PAS protein, CLOCK (circadian locomotor output cycle kaput), which regulates circadian rhythm. ARNTL-CLOCK heterodimer complex activates transcription from E-box (CANNTG) elements found in the promoter of circadian responsive genes. ARNTL is highly homologous to ARNT.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462525240 110 QGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 173
Cdd:cd11438     1 QGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 64

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240  192 HLILRAADGFLFVVGCDrGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQL 251
Cdd:smart00091   4 RAILESLPDGIFVLDLD-GRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEAL 62

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) and similar proteins; ARNTL, also termed Basic-helix-loop-helix-PAS protein MOP3, or brain and muscle ARNT-like 1 (BMAL1), or Class E basic helix-loop-helix protein 5 (bHLHe5), or member of PAS protein 3, or PAS domain-containing protein 3 (PASD3), or bHLH-PAS protein JAP3, is a member of the bHLH-PAS transcription factor family that forms heterodimers with another bHLH-PAS protein, CLOCK (circadian locomotor output cycle kaput), which regulates circadian rhythm. ARNTL-CLOCK heterodimer complex activates transcription from E-box (CANNTG) elements found in the promoter of circadian responsive genes. ARNTL is highly homologous to ARNT.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462525240 110 QGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 173
Cdd:cd11438     1 QGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 64

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 383 VSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTnCYKFKIKDGSFITLRSRW 462
Cdd:cd00130     5 VIVLDLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLSGGEPVTL-EVRLRRKDGSVIWVLVSL 83

                          90
                  ....*....|....*.
gi 2462525240 463 FSFMNPWTKEVEYIVS 478
Cdd:cd00130    84 TPIRDEGGEVIGLLGV 99

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 2462525240  123 IEKRRRDKMNSFIDELASLVPTCNaMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:smart00353   3 RERRRRRKINEAFDELRSLLPTLP-KNKKLSKAEILRLAIEYIKSLQ 48

PAS fold; The PAS fold corresponds to the structural domain that has previously been defined as PAS and PAC motifs. The PAS fold appears in archaea, eubacteria and eukarya. This domain can bind gases (O2, CO and NO), FAD, 4-hydroxycinnamic acid and NAD+ (Matilla et.al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 189 ELKHLILRAADGFLFVVGcDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLSS--SDTAPR---ERLI 263
Cdd:pfam00989   1 EDLRAILESLPDGIFVVD-EDGRILYVNAAAEELLGLSREEVIGKSLLDLIPEEDDAEVAELLRQalLQGEESrgfEVSF 79

                          90       100       110
                  ....*....|....*....|....*....|...
gi 2462525240 264 DAKTGLPVKTDITPGPSRLCSGARRSFFCRMKC 296
Cdd:pfam00989  80 RVPDGRPRHVEVRASPVRDAGGEILGFLGVLRD 112

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2462525240  383 VSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQ 436
Cdd:smart00091  14 IFVLDLDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLLS 67

PAS domain [Signal transduction mechanisms];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2462525240 389 DGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSR 461
Cdd:COG2202   156 DGRILYVNPAAEELLGYSPEELLGKSLLDLLHPEDRERLLELLRRLLEGGRESYELELRLKDGDGRWVWVEAS 228

PAS domain S-box; The PAS domain was previously described. This sensory box, or S-box domain occupies the central portion of the PAS domain but is more widely distributed. It is often tandemly repeated. Known prosthetic groups bound in the S-box domain include heme in the oxygen sensor FixL, FAD in the redox potential sensor NifL, and a 4-hydroxycinnamyl chromophore in photoactive yellow protein. Proteins containing the domain often contain other regulatory domains such as response regulator or sensor histidine kinase domains. Other S-box proteins include phytochromes and the aryl hydrocarbon receptor nuclear translocator. [Regulatory functions, Small molecule interactions]

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 193 LILRAADGFLFVVGcDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLS 252
Cdd:TIGR00229   7 AIFESSPDAIIVID-LEGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIE 65

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) and similar proteins; ARNTL, also termed Basic-helix-loop-helix-PAS protein MOP3, or brain and muscle ARNT-like 1 (BMAL1), or Class E basic helix-loop-helix protein 5 (bHLHe5), or member of PAS protein 3, or PAS domain-containing protein 3 (PASD3), or bHLH-PAS protein JAP3, is a member of the bHLH-PAS transcription factor family that forms heterodimers with another bHLH-PAS protein, CLOCK (circadian locomotor output cycle kaput), which regulates circadian rhythm. ARNTL-CLOCK heterodimer complex activates transcription from E-box (CANNTG) elements found in the promoter of circadian responsive genes. ARNTL is highly homologous to ARNT.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462525240 110 QGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 173
Cdd:cd11438     1 QGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 64

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator (ARNT) family; The ARNT family of bHLH-PAS transcription regulators includes ARNT, ARNT-like proteins (ARNTL and ARNTL2), and Drosophila melanogaster protein cycle. They act as the heterodimeric partner for bHLH-PAS proteins such as aryl hydrocarbon receptor (AhR), hypoxia-inducible factor (HIF), and single-minded (SIM). These bHLH-PAS transcription complexes are involved in transcriptional responses to xenobiotic, hypoxia, and developmental pathways. Heterodimerization of bHLH-PAS proteins with ARNT is mediated by contacts between both the bHLH and the tandem PAS domains. ARNT use bHLH and/or PAS domains to interact with several transcriptional coactivators. It is required for activity of the aryl hydrocarbon (dioxin) receptor. ARNTL, also termed Basic-helix-loop-helix-PAS protein MOP3, or brain and muscle ARNT-like 1 (BMAL1), or Class E basic helix-loop-helix protein 5 (bHLHe5), or member of PAS protein 3, or PAS domain-containing protein 3 (PASD3), or bHLH-PAS protein JAP3, is a member of the bHLH-PAS transcription factor family that forms heterodimers with another bHLH-PAS protein, CLOCK (circadian locomotor output cycle kaput), which regulates circadian rhythm. ARNTL-CLOCK heterodimer complex activates transcription from E-box (CANNTG) elements found in the promoter of circadian responsive genes. ARNTL is highly homologous to ARNT. ARNTL2, also termed Basic-helix-loop-helix-PAS protein MOP9, or brain and muscle ARNT-like 2 (BMAL2), or CYCLE-like factor (CLIF), or Class E basic helix-loop-helix protein 6 (bHLHe6), or member of PAS protein 9, or PAS domain-containing protein 9 (PASD9), is a neuronal bHLH-PAS transcriptional factor, regulating cell cycle progression and preventing cell death, whose sustained expression might ensure brain neuron survival. It also plays important roles in tumor angiogenesis. Protein cycle, also termed brain and muscle ARNT-like 1 (BMAL1), or MOP3, is a putative bHLH-PAS transcription factor involved in the generation of biological rhythms in Drosophila. It activates cycling transcription of Period (PER) and Timeless (TIM) by binding to the E-box (5'-CACGTG-3') present in their promoters.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462525240 116 AREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATN 173
Cdd:cd11437     1 SRSNHSEIEKRRRDKMNAYIQELSALVPACNAMSRKLDKLTVLRMAVQHLKSLRGTGS 58

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator (ARNT) and similar proteins; ARNT, also termed Class E basic helix-loop-helix protein 2 (bHLHe2), or Dioxin receptor, nuclear translocator, or hypoxia-inducible factor 1-beta (HIF1b), or HIF-1-beta, or HIF1-beta, is a member of bHLH-PAS transcription regulators that acts as the heterodimeric partner for bHLH-PAS proteins such as aryl hydrocarbon receptor (AhR), hypoxia-inducible factor (HIF), and single-minded (SIM). These bHLH-PAS transcription complexes are involved in transcriptional responses to xenobiotic, hypoxia, and developmental pathways. Heterodimerization of bHLH-PAS proteins with ARNT is mediated by contacts between both the bHLH and the tandem PAS domains. ARNT use bHLH and/or PAS domains to interact with several transcriptional coactivators. It is required for activity of the aryl hydrocarbon (dioxin) receptor.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2462525240 114 KNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATNP 174
Cdd:cd18947     3 RFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNT 63

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain family; bHLH-PAS domain has been found in a large group of bHLH transcription regulators that are involved in gene expression responding to environmental change and controlling aspects of neural development, including proteins from aryl hydrocarbon receptor nuclear translocator (ARNT) family, hypoxia-inducible factor (HIF) family, aryl hydrocarbon receptor (AhR) family, neuronal PAS domain-containing protein (NPAS) family, Circadian locomotor output cycles protein kaput (CLOCK)-like family, and single-minded (SIM) family. bHLH-PAS transcriptional regulatory factors have a bHLH DNA-binding domain followed by two PAS domains and a C-terminal activation or repression domain. bHLH-PAS family members can be divided into class I and class II based on their dimerization partner. bHLH-PAS class I factors include AhR, HIF and SIM. The best characterized bHLH-PAS Class II protein is the ubiquitous ARNT. Some members of bHLH-PAS family act as transcriptional coactivators (such as NCoA) that lack the ability to dimerize and bind DNA.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2462525240 117 REAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGA 171
Cdd:cd11391     1 REKSREAAKKRRDKENAEISELASLLPLPPAVGSKLDKLSVLRLAVAYLRLKKFL 55

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2462525240 117 REAHSQIEKRRRDKMNSFIDELASLVPTcNAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:pfam00010   2 REAHNERERRRRDRINDAFDELRELLPT-LPPDKKLSKAEILRLAIEYIKHLQ 53

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 2462525240  123 IEKRRRDKMNSFIDELASLVPTCNaMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:smart00353   3 RERRRRRKINEAFDELRSLLPTLP-KNKKLSKAEILRLAIEYIKSLQ 48

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240  192 HLILRAADGFLFVVGCDrGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQL 251
Cdd:smart00091   4 RAILESLPDGIFVLDLD-GRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEAL 62

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 198 ADGFLFVVgCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLSSSDTA----PRERLIDAKTG--LPV 271
Cdd:cd00130     1 LPDGVIVL-DLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLSGgepvTLEVRLRRKDGsvIWV 79

                  ....*.
gi 2462525240 272 KTDITP 277
Cdd:cd00130    80 LVSLTP 85

PAS fold; The PAS fold corresponds to the structural domain that has previously been defined as PAS and PAC motifs. The PAS fold appears in archaea, eubacteria and eukarya.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 392 FVFVDQRATAILAYLPQELLGT--SCYEYFHQDDIGHLAECHRQVLQTREKITTNcYKFKIKDGSFITLRSRWFSFMNPW 469
Cdd:pfam08447   1 IIYWSPRFEEILGYTPEELLGKgeSWLDLVHPDDRERVREALWEALKGGEPYSGE-YRIRRKDGEYRWVEARARPIRDEN 79

                  ....*..
gi 2462525240 470 TKEVEYI 476
Cdd:pfam08447  80 GKPVRVI 86

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in the aryl hydrocarbon receptor (AhR) family; The AhR family includes AhR, AhR repressor (AhRR) and Drosophila melanogaster protein spineless. AhR, also termed Ah receptor, or Dioxin receptor (DR), or Class E basic helix-loop-helix protein 76 (bHLHe76), is the only member of bHLH-PAS transcription regulators that bind and be activated by small chemical ligands. It is activated by Dioxin to control the expression of certain genes to influence biological processes such as apoptosis, proliferation, cell growth and differentiation. To form active DNA binding complexes AhR dimerizes with a bHLH-PAS factor ARNT (Aryl hydrocarbon Nuclear Receptor Translocator). AhRR, also termed Class E basic helix-loop-helix protein 77 (bHLHe77), is a member of bHLH-PAS transcription factors that acts as a negative regulator of AhR, playing key roles in development and environmental sensing. AhRR functions by competing with AhR for its partner ARNT. AhRR-ARNT complexes are transcriptionally inactive. Spineless is a bHLH-PAS transcription factor that plays an important role in fly morphogenesis. It is both necessary and sufficient for the formation of the ommatidial mosaic.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2462525240 125 KRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKT 167
Cdd:cd19696     9 KRHRDRLNSELDELASLLPFPEDVISKLDKLSVLRLSVSYLRT 51

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split (HES) family; The HES family includes bHLH-O transcriptional regulators that are related to the Drosophila hairy and Enhancer-of-split (HES) proteins. They contain a basic helix-loop-helix (bHLH) domain with an invariant proline residue in its basic region, an orange domain in the central region and a conserved tetrapeptide motif, WRPW, at its C-terminal region. HES family proteins form heterodimers or homodimers via their HLH domain and bind DNA to repress gene transcription that play an essential role in development of both compartment and boundary cells of the central nervous system.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462525240 123 IEKRRRDKMNSFIDELASLVPTC----NAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd11410     1 MEKKRRARINKSLEQLKTLVLEAlnkdNTRYSKLEKADILEMTVKYLKQLQ 51

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif-like protein (HEYL) and similar proteins; HEYL, also termed Class B basic helix-loop-helix protein 33 (bHLHb33), or hairy-related transcription factor 3 (HRT-3), is a bHLH-O transcriptional repressor that is strongly expressed in the presomitic mesoderm, the somites, the peripheral nervous system and smooth muscle of all arteries and is a downstream effector of the Notch and transforming growth factor-beta pathways. It promotes neuronal differentiation by activating proneural genes and inhibiting other hairy and enhancer of split (HES) and hairy/enhancer-of-split related with YRPW motif protein (HEY) proteins. HEYL also functions as a tumor suppressor involved in the progression of human cancers.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462525240 116 AREAHSQI-EKRRRDKMNSFIDELASLVPTC--NAMSRKLDKLTVLRMAVQHMKTL 168
Cdd:cd11447     8 ARKKRRGIiEKRRRDRINSSLSELRRLVPTAfeKQGSSKLEKAEILQMTVDHLKML 63

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana genes coding transcription factors and similar proteins; bHLH proteins are the second largest class of plant transcription factors that regulate transcription of genes that are involve in many essential physiological and developmental process. bHLH proteins are transcriptional regulators that are found in organisms from yeast to humans. The Arabidopsis bHLH proteins that have been characterized so far have roles in regulation of fruit dehiscence, cell development (carpel, anther and epidermal), phytochrome signaling, flavonoid biosynthesis, hormone signaling and stress responses.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462525240 120 HSQIEKRRRDKMNSFIDELASLVPTCNamsrKLDKLTVLRMAVQHMKTLR 169
Cdd:cd11393     1 HSIAERKRREKINERIRALRSLVPNGG----KTDKASILDEAIEYIKFLQ 46

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) and similar proteins; HEY1, also termed cardiovascular helix-loop-helix factor 2 (CHF-2), or Class B basic helix-loop-helix protein 31 (bHLHb31), or HES-related repressor protein 1, or hairy and enhancer of split-related protein 1 (HESR-1), or hairy-related transcription factor 1 (HRT-1), is a bHLH-O transcriptional repressor that acts as an essential downstream effector of the Notch signaling pathway and may play a fundamental role in vascular development. HEY1 also participates several cancer-related pathways. It acts as a positive regulator of the tumor suppressor p53.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462525240 123 IEKRRRDKMNSFIDELASLVPTC--NAMSRKLDKLTVLRMAVQHMKTLRGA 171
Cdd:cd19748    16 IEKRRRDRINNSLSELRRLVPSAfeKQGSAKLEKAEILQMTVDHLKMLHAA 66

basic helix-loop-helix-orange (bHLH-O) domain found in HERP/HES-like family; The HERP/HES-like family includes bHLH-O transcriptional regulators that are related to the Drosophila hairy and Enhancer-of-split (HES) proteins. The HERP (HES-related repressor protein) subfamily proteins contain a basic helix-loop-helix (bHLH) domain with an invariant glycine residue in its basic region, an orange domain in the central region and YXXW sequence motif at its C-terminal region. Hairy and enhancer of split (HES)-related repressor protein (HERP) proteins (HEY1, HEY2 and HEYL) act as downstream effectors of Notch signaling. They are involved in cardiovascular development and have roles in somitogenesis, myogenesis and gliogenesis. Hairy and enhancer of split-related protein HELT is a transcriptional repressor expressed in the developing central nervous system. It binds preferentially to the canonical E box sequence 5'-CACGCG-3' and regulates neuronal differentiation and/or identity. Differentially expressed in chondrocytes proteins, DEC1 and DEC2, are widely expressed in both embryonic and adult tissues and have been implicated in apoptosis, cell proliferation, and circadian rhythms, as well as malignancy in various cancers. Drosophila melanogaster protein clockwork orange (Cwo) is also included in this subfamily. It is involved in the regulation of Drosophila circadian rhythms. It functions as both an activator and a repressor of clock gene expression. The HES subfamily proteins contain a basic helix-loop-helix (bHLH) domain with an invariant proline residue in its basic region, an orange domain in the central region and a conserved tetrapeptide motif, WRPW, at its C-terminal region. They form heterodimers or homodimers via their HLH domain and bind DNA to repress gene transcription that play an essential role in development of both compartment and boundary cells of the central nervous system.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462525240 123 IEKRRRDKMNSFIDELASLVPTCNAM--SRKLDKLTVLRMAVQHMKTLRGA 171
Cdd:cd19685     1 SEKRRRQRINDKLNQLKELLPPNLSKqsRSKLSKAEILEMAITELRRLQQE 51

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factors, USF1, USF2 and similar proteins; Upstream stimulatory factor 1 and 2 (USF-1 and USF-2) are members of bHLHzip transcription factor family. USFs are ubiquitously expressed and key regulators of a wide number of gene regulation networks, including the stress and immune responses, cell cycle and proliferation, lipid and glucid metabolism. USFs recruit chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. USFs interact with high affinity to E-box regulatory elements.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2462525240 120 HSQIEKRRRDKMNSFIDELASLVPTCN--AMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd11396     2 HNEVERRRRDKINNWIVKLAKIVPDCEkdNSKQGQSKGGILSKACDYIQELR 53

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor repressor (AhRR) and similar proteins; AhRR, also termed AhR repressor, or Class E basic helix-loop-helix protein 77 (bHLHe77), is a member of bHLH-PAS transcription factors that acts as a negative regulator of AhR (or Dioxin Receptor), playing key roles in development and environmental sensing. AhR is activated by Dioxin to control the expression of certain genes to influence biological processes such as apoptosis, proliferation, cell growth and differentiation. To form active DNA binding complexes, AhR dimerizes with a bHLH-PAS factor ARNT (Aryl hydrocarbon Nuclear Receptor Translocator). AhRR functions by competing with AhR for its partner ARNT. AhRR-ARNT complexes are transcriptionally inactive.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2462525240 121 SQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMK 166
Cdd:cd11435     5 SNPSKRHRDRLNAELDHLASLLPFPPDIISKLDKLSVLRLSVSYLR 50

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana phytochrome interacting factors (PIFs) and similar proteins; The family includes several bHLH transcription factors from Arabidopsis thaliana, such as PIFs, ALC, PIL1, SPATULA, and UNE10. PIFs (PIF1, PIF3, PIF4, PIF5, PIF6 and PIF7) have been shown to control light-regulated gene expression. They directly bind to the photoactivated phytochromes and are degraded in response to light signals. ALC, also termed AtbHLH73, or protein ALCATRAZ, or EN 98, is required for the dehiscence of fruit, especially for the separation of the valve cells from the replum. It promotes the differentiation of a strip of labile non-lignified cells sandwiched between layers of lignified cells. PIL1, also termed AtbHLH124, or protein phytochrome interacting factor 3-like 1, or EN 110, is involved in responses to transient and long-term shade. It is required for the light-mediated inhibition of hypocotyl elongation and necessary for rapid light-induced expression of the photomorphogenesis- and circadian-related gene APRR9. PIL1 seems to play a role in multiple PHYB responses, such as flowering transition and petiole elongation. SPATULA, also termed AtbHLH24, or EN 99, plays a role in floral organogenesis. It promotes the growth of carpel margins and of pollen tract tissues derived from them. UNE10, also termed AtbHLH16, or protein UNFERTILIZED EMBRYO SAC 10, or EN 99, is required during the fertilization of ovules by pollen.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2462525240 116 AREAHSQIEKRRRDKMNSFIDELASLVPTCNamsrKLDKLTVLRMAVQHMKTL 168
Cdd:cd11445     2 AAEVHNLSERRRRDRINEKMKALQELIPNCN----KTDKASMLDEAIEYLKSL 50

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in basic helix-loop-helix domain-containing protein USF3 and similar proteins; USF3, also termed upstream transcription factor 3, is a bHLHzip protein that is involved in the negative regulation of epithelial-mesenchymal transition, the process by which epithelial cells lose their polarity and adhesion properties to become mesenchymal cells with enhanced migration and invasive properties.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462525240 114 KNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAmsRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd18910     3 EKKRESHNEVERRRKDKINAGINKIGELLPDRDA--KKQSKNMILEQAYKYIVELK 56

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in the microphthalmia-associated transcription factor family (MITF) family; The MITF (also known as microphthalmia-TFE, or MiT) family is a small family that contain a basic helix loop helix domain associated with a leucine zipper (bHLHZip). The MITF family comprises four genes in mammals (MITF, TFE3, TFEB, and TFEC); each gene has different functions. MITF is involved in neural crest melanocytes development as well as the pigmented retinal epithelium. TFEB is required for vascularization of the mouse placenta. TFE3 is involved in B cell function. TFEC regulates gene expression in macrophages. The MITF family can form homodimers or heterodimers with each other but not with other bHLH or bHLHzip proteins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462525240 112 RIKnaREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd11397     3 RQK--KDNHNMIERRRRFNINDRIKELGTLLPKSNDPDMRWNKGTILKASVDYIRKLQ 58

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) and similar proteins; HEY2, also termed cardiovascular helix-loop-helix factor 1 (CHF-1), or Class B basic helix-loop-helix protein 32 (bHLHb32), or HES-related repressor protein 2, or hairy and enhancer of split-related protein 2 (HESR-2), or hairy-related transcription factor 2 (HRT-2), or protein gridlock homolog, is a bHLH-O transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. As a downstream effector of Notch signaling, HEY2 may be required for cardiovascular development. It also plays an important role in neurologic development, as well as in the progression of human cancers.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462525240 123 IEKRRRDKMNSFIDELASLVPTC--NAMSRKLDKLTVLRMAVQHMKTLRG 170
Cdd:cd18920    17 IEKRRRDRINNSLSELRRLVPTAfeKQGSAKLEKAEILQMTVDHLKMLQA 66

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Drosophila melanogaster protein spineless and similar proteins; Spineless is a bHLH-PAS transcription factor that plays an important role in fly morphogenesis. It is both necessary and sufficient for the formation of the ommatidial mosaic.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2462525240 121 SQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKT 167
Cdd:cd19730     8 SNPSKRHRERLNAELDHLASLLPFEQSVISKLDKLSILRLSVSYLRT 54

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factor 1 (USF1) and similar proteins; USF1, also termed Class B basic helix-loop-helix protein 11 (bHLHb11), or major late transcription factor 1, is a bHLHzip transcription factor that binds to a symmetrical DNA sequence (E-boxes) (5'-CACGTG-3') that is found in a variety of viral and cellular promoters. It is ubiquitously expressed and involved in the transcription activation of various functional genes implicated in lipid and glucose metabolism, stress response, immune response, cell cycle control and tumour suppression. USF-1 recruits chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. Genetic polymorphisms of USF1 are associated with some metabolic and cardiovascular diseases, like diabetes, atherosclerosis, coronary artery calcifications and familial combined hyperlipidaemia (FCHL).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 112 RIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKL--DKLTVLRMAVQHMKTLR 169
Cdd:cd18924     1 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSgqSKGGILSKACDYIQELR 60

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor EB (TFEB) and similar proteins; TFEB, also termed Class E basic helix-loop-helix protein 35 (bHLHe35), is a bHLHzip transcription factor that is required for vascularization of the mouse placenta. It specifically recognizes and binds E-box sequences (5'-CANNTG-3'). Its efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462525240 114 KNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd18927     9 RQKKDNHNLIERRRRFNINDRIKELGTLIPKTNDLDVRWNKGTILKASVDYIKRMQ 64

basic helix-loop-helix (bHLH) domain found in transcription factor-like 5 protein (TCFL5) and similar proteins; TCFL5, also termed Cha transcription factor, or HPV-16 E2-binding protein 1 (E2BP-1), is a bHLH transcription factor that plays a crucial role in spermatogenesis. It regulates cell proliferation or differentiation of cells through binding to a specific DNA sequence like other bHLH molecules.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2462525240 117 REAHSQIEKRRRDKMNSFIDELASLVPTCNAMSrklDKLTVLRMAVQHMKTLRG 170
Cdd:cd18909     3 RERHNRMERDRRRRIRICCDELNLLVPFCNAET---DKATTLQWTTAFLKYIQE 53

PAS domain [Signal transduction mechanisms];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2462525240 389 DGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSR 461
Cdd:COG2202   156 DGRILYVNPAAEELLGYSPEELLGKSLLDLLHPEDRERLLELLRRLLEGGRESYELELRLKDGDGRWVWVEAS 228

basic helix-loop-helix (bHLH) domain found in the spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein (SOHLH) family; The SOHLH family includes two bHLH transcription factors, SOHLH1 and SOHLH2. They are specifically in spermatogonia and oocytes and essential for early spermatogonial and oocyte differentiation.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462525240 120 HSQIEKRRRDKMNSFIDELASLVPtcNAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd18908     6 HSLKERLRRERIKSSCDQLRDLLP--YIKGRKLDMASVLEMTVKYIRYIQ 53

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor EC (TFEC) and similar proteins; TFEC, also termed Class E basic helix-loop-helix protein 34 (bHLHe34), or transcription factor EC-like (TFEC-L), is a bHLHzip transcriptional regulator that acts as a repressor or an activator and regulates gene expression in macrophages. It plays an important role in the niche to expand hematopoietic progenitors through the modulation of several cytokines.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462525240 114 KNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd18925     3 RQKKDNHNLIERRRRYNINYRIKELGTLIPKSNDPDMRWNKGTILKASVEYIKWLQ 58

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in sterol regulatory element-binding protein 1 (SREBP1) and similar proteins; SREBP1, also termed Class D basic helix-loop-helix protein 1 (bHLHd1), or sterol regulatory element-binding transcription factor 1 (SREBF1), is a member of a family of bHLHzip transcription factors that recognize sterol regulatory element 1 (SRE-1). It acts as a transcriptional activator required for lipid homeostasis. It may control transcription of the low-density lipoprotein receptor gene as well as the fatty acid. SREBP1 has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3').

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2462525240 117 REAHSQIEKRRRDKMNSFIDELASLVPTCNAmsrKLDKLTVLRMAVQHMKTLRGATNPYTEAN 179
Cdd:cd18921     7 RTAHNAIEKRYRSSINDKIIELKDLVVGTEA---KLNKSAVLRKAIDYIRFLQQSNQKLKQEN 66

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor E3 (TFE3) and similar proteins; TFE3, also termed Class E basic helix-loop-helix protein 33 (bHLHe33), is a bHLHzip transcription factor that is involved in B cell function. It specifically recognizes and binds E-box sequences (5'-CANNTG-3'). Its efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFEB or MITF.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462525240 114 KNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd18928     9 RQKKDNHNLIERRRRFNINDRIKELGTLIPKSTDPEMRWNKGTILKASVDYIRKLQ 64

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Saccharomyces cerevisiae transcription factor HMS1 and similar proteins; HMS1, also termed high-copy MEP suppressor protein 1, is a putative bHLHzip transcription factor involved in exit from mitosis and pseudohyphal differentiation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 117 REAHSQIEKRRRDKMNSFIDELASLVPTCNAMS-------------------RKLDKLTVLRMAVQHMKTLRGATNPYTE 177
Cdd:cd11399     4 KTAHNMIEKRYRSNINDRIAELRDSVPALREAYksargededeedlggltpaTKLNKATILSKATEYIRHLEKKNKRLSR 83

                  ..
gi 2462525240 178 AN 179
Cdd:cd11399    84 EN 85

PAS domain S-box; The PAS domain was previously described. This sensory box, or S-box domain occupies the central portion of the PAS domain but is more widely distributed. It is often tandemly repeated. Known prosthetic groups bound in the S-box domain include heme in the oxygen sensor FixL, FAD in the redox potential sensor NifL, and a 4-hydroxycinnamyl chromophore in photoactive yellow protein. Proteins containing the domain often contain other regulatory domains such as response regulator or sensor histidine kinase domains. Other S-box proteins include phytochromes and the aryl hydrocarbon receptor nuclear translocator. [Regulatory functions, Small molecule interactions]

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462525240 193 LILRAADGFLFVVGcDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLS 252
Cdd:TIGR00229   7 AIFESSPDAIIVID-LEGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIE 65

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in MLX-interacting protein (MLXIP), MLX-interacting protein-like (MLXIPL) and similar proteins; The family includes MLXIP and MLXIPL. MLXIP, also termed Class E basic helix-loop-helix protein 36 (bHLHe36), or transcriptional activator MondoA, is a bHLHZip transcriptional activator that binds DNA as a heterodimer with Mlx. It binds to the canonical E box sequence 5'-CACGTG-3' and plays a role in transcriptional activation of glycolytic target genes. MLXIP is most highly expressed in skeletal muscle and functions as an indirect glucose sensor, by sensing glucose 6-phosphate and shuttling between the nucleus and the cytoplasm. MLXIPL, also termed carbohydrate-responsive element-binding protein (ChREBP), or Class D basic helix-loop-helix protein 14 (bHLHd14), or MLX interactor, or WS basic-helix-loop-helix leucine zipper protein (WS-bHLH), or Williams-Beuren syndrome chromosomal region 14 protein (WBSCR14), is a bHLHZip transcriptional factor integral to the regulation of glycolysis and lipogenesis in the liver. It forms heterodimers with the bHLHZip protein Mlx to bind the DNA sequence 5'-CACGTG-3'.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2462525240 117 REAHSQIEKRRRDKMNSFIDELASLVPTCNAM-SRKLDKLTVLRMAVQHMKTLR 169
Cdd:cd11405     4 RLSHISAEQKRRFNIKSGFDTLQSLIPSLGQNpNQKVSKAAMLQKAAEYIKSLK 57

basic helix-loop-helix-orange (bHLH-O) domain found in differentially expressed in chondrocytes protein 2 (DEC2) and similar proteins; DEC2, also termed Class E basic helix-loop-helix protein 41 (bHLHe41), or Class B basic helix-loop-helix protein 3 (bHLHb3), or enhancer-of-split and hairy-related protein 1 (SHARP-1), is a bHLH-O transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2462525240 120 HSQIEKRRRDKMNSFIDELASLVPTCNAMSR--KLDKLTVLRMAVQHMKTLRGAT 172
Cdd:cd19750    19 HRLIEKKRRDRINECIAQLKDLLPEHLKLTTlgHLEKAVVLELTLKHLKALTALT 73